Mesenchymal stem cells (MSCs) are multipotent progenitors that have the abilities of self-renewal and multiple direction differentiation. The osteogenic potential of MSCs holds great promise for bone defect repair and bone disease treatment. For a long time studies about osteogenic differentiation of MSCs have emphasized on the effect of extrinsic regulators and the corresponding transcription factors controlling cell fate. In fact, cell fate is determined by lineage specific gene expression that is regulated more specifically by epigenetic mechanism. Over the last decade, some progress has been made in epigenetic researches of MSCs osteogenic differentiation. DNA methylation, histone modifications and microRNA (miRNA) are all verified important mechanisms regulating MSCs differentiation. Epigenetic regulation might provide novel treatment targets for promoting bone formation. In this review, we will summarize the recent advance about the epigenetic mechanism that control MSCs commitment to osteoblasts and the potential clinical application of MSCs epigenetics in future.